Vasodilator drugs are used in several conditions involving tissue ischemia with the most important indication being angina pectoris. Atherosclerosis is involved in most cases of angina pectoris. In recent years a number of studies have revealed important information about the effects of estrogens on the cardiovascular system. Experiments in animals (Haarbo J et al. J Clin Invest 1991; 87:1294-1279) and epidemiologic studies in humans (PEPI trial, JAMA 1995; 273:199-208) have demonstrated that estrogens possess antiatherogenic properties and it has been speculated that the decreased cardiovascular morbidity and mortality seen in women between 35 and 50 compared to men, is due to an intact ovarian function with the production of estrogens. It has also been demonstrated that estrogens possess vasodilator properties, at least when administered in test systems in pharmacological doses. Estrogens and estrogen receptor stimulation may therefore have a dual mechanism which may act synergistically on the pathologic mechanisms involved in tissue ischemia.
Recent studies (Writing group for the PEPI trial, JAMA 273:199, 1955) confirm that oral estrogen taken alone or in combination with medroxy-progesterone acetate or micronized progesterone is associated with a beneficial effect on the risk of developing cardiovascular disease. However, estrogen is also known to have adverse effects on endometrium and perhaps breast tissue by increasing the frequency of malignancies in these areas after prolonged treatment.
Thus, there is a need for a new compound which has the beneficial vasodilatory effect of estrogen, but without introducing significant effects on the reproductive tissues.
Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinol. (Copenh) 126 (1992), 444-450; Grubb, Curr. Opin. Obstet. Gynecol. 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781-783). Recently, centchroman as a racemate has been found potent as a cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J. Min. Bon. Res. 9 (1994), 394).
U.S. Pat. No. 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts.
One object of the present invention is to provide compounds which can effectively be used in the vasodilatory treatment or prophylaxis of e.g. cerebral ischaemia, angina pectoris or Raynaud's syndrome.